Tau pathology is implicated as a pathogenic factor in a number of neurodegenerative disorders. Mutations in the tau gene cause some familial cases of frontotemporal lobe dementia, which occurs without concomitant amyloid pathology. The Tg4510 mouse is a transgenic model based on one of these mutations in tau. It is an aggressive model of tauopathy and results in age-dependent tau deposition, behavioral disturbance and neurodegeneration in multiple forebrain structures. Immunotherapy is rapidly advancing with almost 30 FDA approved medications. Immunotherapy is also one of the most advanced anti-amyloid approaches. Multiple clinical trials are testing anti-A immunotherapy as a treatment for dementia. Our group supplied the bulk of the preclinical mouse data supporting the use of one of these agents being pursued in the clinic by Pfizer. Although less extensively examined, presently there are only a few therapeutic strategies targeting tau as a treatment for dementia. Given the broader involvement of tau in neurodegenerative disorders than amyloid, approaches targeting this peptide may have even greater impact than anti-amyloid strategies. This application will investigate the use of anti-tau antibodies as an approach to removing tau deposits in the Tg4510 mouse model. Preliminary data shows that a single intracranial injection of an antibody directed against all forms of tau (tau-5, mid domain epitope IgG1, not phosphorylation specific) can reduce histologically identified tau and reduce silver stained deposits identified by Gallyas. We wish to pursue this initial observation to address 4 specific aims. The first aim will examine the efficacy of 9 different antibodies from 3 different categories using intracranial injections. The first category is antibodies binding all isoforms of tau, like the tau-5 antibody which was successful in the preliminary data. The second category is antibodies targeting specific phosphorylated residues on tau. In a different tau model, Sigurdsson's group has shown vaccines targeting phospho-forms of tau can reduce tau deposition (ref in application). The third category of antibodies targets specific modifications of tau, including conformational changes, nitration and truncation. These latter antibodies might have a greater safety profile, if effective, as they should not target tau isoforms involved with regulation of axonal transport. The second aim will test whether some of these antibodies can prevent further tau deposition using young mice and systemic administration. Aim 3 will test if the systemic route of administration can remove pre-existing tau deposits using systemic administration in older mice. Aim 4 will test the hypothesis that combining intracranial injections to clear pre-existing deposits and following up with systemic administration to prevent formation of new deposits is a superior strategy than either alone. PUBLIC HEALTH RELEVANCE: A protein called tau accumulates in the brain of many humans who develop age-associated brain diseases. The deposited tau causes death of neurons and impairs normal brain function. Diseases include Pick's disease, frontotemporal lobe dementia and Alzheimer's disease. These experiments will use antibodies that bind to the tau protein in an attempt to eliminate it from the brain. This may lead to use of similar antibodies or possible vaccines to treat patients with these diseases.